Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

ATM and RPA in meiotic chromosome synapsis and recombination

Nature Genetics volume 17, pages 457–461 (1997)Cite this article

Abstract

ATM is a member of the phosphatidylinositol 3-kinase (PIK)like kinases, some of which are active in regulating DNA damage-induced mitotic cell-cycle checkpoints1,2. ATM also plays a role in meiosis. Spermatogenesis in Atm−/− male mice is disrupted, with chromosome fragmentation leading to meiotic arrest3; in human patients with ataxia-telangiectasia (A-T), gonadal atrophy is common. Immuno-localization studies indicate that ATM is associated with sites along the synaptonemal complex (SC), the specialized structure along which meiotic recombination occurs4. Recombination, preceded by pairing of homologous chromosomes, is thought to require heteroduplex formation between homologous DNA, followed by strand exchange. These early meiotic steps (entailing the formation and processing of meiotic recombination intermediates with DNA-strand interruptions) require ssDNA-binding proteins such as replication protein A (RPA; refs 5-7). In somatic cells, DNA damage induces ATM-dependent phosphorylation of RPA8,9. We demonstrate here that ATM and RPA co-localize along synapsed meiotic chromosomes and at sites where interactions between ectopic homologous chromosome regions appear to initiate. In Atm−/− meiotic prophase sper-matocytes, immuno-localization shows that RPA is present along synapsing chromosomes and at sites of fragmentation of the SC. These results suggest that RPA and ATM co-localize at sites where interhomologous-DNA interactions occur during meiotic prophase and where breaks associated with meiotic recombination take place after synapsis, implying a possible functional interaction between these two proteins.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Savitsky, K. et al. A single ataxia telangiectasia gene with a product similar to Pl-3 kinase. Science 268, 1749–1753 (1995).

    Article  CAS  Google Scholar 

  2. Hoekstra, M.F. Responses to DMA damage and regulation of cell cycle checkpoints by the ATM protein kinase family. Curr. Opin. Genet. Dev. 7, 170–175 (1997).

    Article  CAS  Google Scholar 

  3. Xu, Y. et al. Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev. 10, 2411–2422 (1996).

    Article  CAS  Google Scholar 

  4. Keegan, K.S. et al. The Atr and Atm protein kinases associate with different sites along meiotically pairing chromosomes. Genes Dev. 10, 2423–2437 (1996).

    Article  CAS  Google Scholar 

  5. Baumann, P., Benson, F.E. & West, S.C., Rad51 protein promotes ATP-dependent homologous pairing and strand transfer reactions in vitro. Cell 87, 757–766 (1996).

    Article  CAS  Google Scholar 

  6. Cox, M.M. & Lehman, I.R. recA protein-promoted DMA strand exchange: stable complexes of recA protein and single-stranded DMA formed in the presence of ATP and single-stranded DNA binding protein. J. Biol. Chem. 257, 8523–8532 (1982).

    CAS  PubMed  Google Scholar 

  7. Flory, J. & Radding, C.M. Visualization of recA protein and its association with DNA: a priming effect of single-stranded binding protein. Cell 28, 747–756 (1982).

    Article  CAS  Google Scholar 

  8. Liu, V.F. & Weaver, D.T. The ionizing radiation-induced replication protein A phosphorylation response differs between ataxia telangiectasia and normal human cells. Mol. Cell. Biol. 13, 7222–7231 (1993).

    Article  CAS  Google Scholar 

  9. Brush, G.S., Morrow, D.M., Hieter, P. & Kelly, T.J. The ATM homologue MEC1 is required for phosphorylation of replication protein A in yeast. Proc. Natl.Acad. Sci. USA 93, 15075–15080 (1996).

    Article  CAS  Google Scholar 

  10. Dobson, M.J., Pearlman, R.E., Karaiskakis, A., Spyropoulous, B. & Moens, P.B. SC proteins, epitope mapping and chromosome disjunction. J. Cell Sci. 107, 2749–2760 (1994).

    CAS  PubMed  Google Scholar 

  11. Ashley, T. et al. Dynamic changes in Rad51 distribution on chromatin during meiosis in male and female vertebrates. Chromosoma 104, 19–28 (1995).

    Article  CAS  Google Scholar 

  12. Plug, A.W., Xu, J., Reedy, G., Golub, E.I. & Ashley, T. Presynaptic association of Rad51 protein with selected sites in meiotic chromatin. Proc. Natl. Acad. Sci. USA 93, 5920–5924 (1996).

    Article  CAS  Google Scholar 

  13. de Boer, P., Searl, A.G., van der Hoeven, F.A., de Rooij, D.G. & Beechey, C.V. Male pachytene pairing in single and double translocation heterozygotes and spermatogenic impairment in the mouse. Chromosoma 93, 326–336 (1986).

    Article  CAS  Google Scholar 

  14. Peters, A.H.F.M., Plug, A.W. & de Boer, P. Meiosis in carriers of heteromorphic bivalents: sex differences and implications for male fertility. Chromosome Res. 5, 313–324 (1997).

    Article  CAS  Google Scholar 

  15. Padmore, R., Cao, L.,& Kleckner, N. Temporal comparison of recombination and SC formation during meiosis in S. cerevisiae. Cell 66, 1239–1256 (1991).

    Article  CAS  Google Scholar 

  16. Keeney, S., Giroux, C. & Kleckner, N. Meiosis-specific DNA double-strand breaks are catalyzed by Spo1l, a member of a widely conserved protein family. Cell 88, 375–384 (1997).

    Article  CAS  Google Scholar 

  17. Sun, H.D., Treco, D., Schultes, N.P. & Szostak, J.W. Double-strand breaks at an initiation site for meiotic gene conversion. Nature 338, 87–90 (1989).

    Article  CAS  Google Scholar 

  18. Cao, L., Alani, E. & Kleckner, N. A pathway for generation and processing of double-strand breaks during meiotic recombination in Scerevisiae. Cell 61, 1089–1101 (1990).

    Article  CAS  Google Scholar 

  19. Shinohara, A., Ogawa, H. & Ogawa, T. Rad51 protein involved in repair and recombination in S. cerevisiae is a RecA-like protein. Cell 69, 457–470 (1992).

    Article  CAS  Google Scholar 

  20. Bishop, D.K., Park, D., Xu, L. & Kleckner, N. DMC1: a meiotic specific yeast homolog of E coli recA required for recombination, SC formation and cell cycle progression. Cell 69, 439–456 (1992).

    Article  CAS  Google Scholar 

  21. Hotta, Y., Ito, M. & Stern, H. Synthesis of DNA during meiosis. Proc. Natl. Acad. Sci. USA 56, 1184–1191 (1966).

    Article  CAS  Google Scholar 

  22. Hotta, Y. & Stern, H. Analysis of DNA synthesis during meiotic prophase in Lilium. J. Mol. Biol. 55, 337–355 (1971).

    Article  CAS  Google Scholar 

  23. Peters, A.H.F.M., Plug, A.W., van Vugt, M.J. & de Boer, P. A drying-down technique for the spreading of mammalian meiocytes from the male and female germ line. Chromosome Res. 5, 66–68 (1997).

    Article  CAS  Google Scholar 

  24. Xu, Y. & Baltimore, D. Dual roles of ATM in the cellular response to radiation and in cell growth control. Genes Dev. 10, 2401–2410 (1996).

    Article  CAS  Google Scholar 

  25. He, Z., Henricksen, L.A., Wold, M.S. & Ingles, C.J. RPA involvement in the damage-recognition and incision steps of nucleotide excision repair. Nature 374, 566–569 (1995).

    Article  CAS  Google Scholar 

  26. Kenny, M.K., Schlegel, U., Furneaux, H. & Hurwitz, J. The role of human single-stranded DNA binding protein and its individual subunits in simian virus 40 DNA replication. J. Biol. Chem. 265, 7693–7700 (1990).

    CAS  PubMed  Google Scholar 

  27. Ried, T., Baldini, A., Rand, T. & Ward, D.C. Simultaneous visualization of seven different DNA probes by in situ hybridization using combinatorial fluorescence and digital imaging microscopy. Proc. Natl. Acad. Sci. USA 89, 1388–1392 (1992).

    Article  CAS  Google Scholar 

  28. Moses, M.J. in Animal Models in Human Reproduction (eds Serio, M. & Martini, L) 169–190 (Raven, New York, 1980).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut, 06510, USA

    Annemieke W. Plug & Terry Ashley

  2. Department of Genetics, Wageningen Institute of Animal Sciences, Wageningen Agricultural University, Wageningen, The Netherlands

    Antoine H.F.M Peters & Peter de Boer

  3. Department of Biology, University of California, San Diego, California, 92093, USA

    Yang Xu

  4. ICOS Corporation, Bothell, Washington, 98021, USA

    Kathleen S. Keegan & Merl F. Hoekstra

  5. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA

    David Baltimore

Authors
  1. Annemieke W. Plug
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Antoine H.F.M Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kathleen S. Keegan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Merl F. Hoekstra
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David Baltimore
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peter de Boer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Terry Ashley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Terry Ashley.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Plug, A., Peters, A., Xu, Y. et al. ATM and RPA in meiotic chromosome synapsis and recombination. Nat Genet 17, 457–461 (1997). https://doi.org/10.1038/ng1297-457

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1297-457

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing